Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is a widely used anticonvulsant drug that is currently undergoing clinical evaluation for anticancer therapy due to its anti-angiogenic potential. Endothelial cells (ECs) can transition into mesenchymal cells and this form of EC plasticity is called endothelial-to-mesenchymal transition (EndMT), which is widely implicated in several pathologies including cancer and organ fibrosis. However, the effect of VPA on EC plasticity and EndMT remains completely unknown. We report herein that VPA-treatment significantly inhibits tube formation, migration, nitric oxide production, proliferation and migration in ECs. A microscopic evaluation revealed, and qPCR, immunofluorescence and immunoblotting data confirmed EndMT-like phenotypic switching as well as an increased expression of pro-fibrotic genes in VPA-treated ECs. Furthermore, our data confirmed important and regulatory role played by TGFβ-signaling in VPA-induced EndMT. Our qPCR array data performed for 84 endothelial genes further supported our findings and demonstrated 28 significantly and differentially regulated genes mainly implicated in angiogenesis, endothelial function, EndMT and fibrosis. We, for the first time report that VPA-treatment associated EndMT contributes to the VPA-associated loss of endothelial function. Our data also suggest that VPA based therapeutics may exacerbate endothelial dysfunction and EndMT-related phenotype in patients undergoing anticonvulsant or anticancer therapy, warranting further investigation.
Age is one of the greatest risk factors for cardiovascular disease, which is the leading cause of death in the developed world. Therefore, the maintenance of cardiac health throughout the lifespan is of the upmost importance. Aging is associated with a plethora of biochemical and metabolic alterations, many of which converge on the mitochondrion. As a highly oxidative tissue, mitochondria supply roughly 95% of all ATP required in the myocardium. This reliance on mitochondria underscores the importance of maintaining the quality of these organelles, especially with age, however little is known about how age effects quality control mechanisms in the human heart. We hypothesized that the removal of mitochondria through mitochondrial specific autophagy, or mitophagy, would be impaired in aged human cardiac tissue. To evaluate mitochondrial quality control, samples of right atria were collected from young (≤50 years) and aged (≥70 years) patients undergoing coronary artery bypass surgery (CABG). Tissue was collected prior to and immediately following surgery, providing a useful model of ischemia‐reperfusion injury. Patients were matched for hyperention and dyslipidemia, as well as prescribed medications such as statins, and ACE inhibitors. Exclusion criteria included smoking, a prior stroke or myocardial infarction, or other comorbidities (e.g. diabetes, cancer). Mitochondrial content as indicated by various markers such as COX IV, VDAC, and UQCRC2 was reduced in the aged samples, however a modest 1.2‐fold increase in Citrate Synthase was observed, suggesting age‐associated compositional changes. The upstream marker of autophagy Beclin‐1 and the transcriptional regulators TFEB and TFE3 did not change with age, suggesting that aging does not affect the drive for autophagy. Despite this, constituents of the autophagosome p62 and LC3‐II were reduced by 20% and 30%, respectively, in the aged samples, indicative of increased autophagy flux. The mitophagy marker Parkin displayed a trend to decrease with age, suggesting a decline in the signaling for mitophagy. The lysosomal marker Cathepsin D was unaffected by age in cardiac muscle, but the lysosomal calcium channel Mucolipin‐1 increased in aged atrial muscle by 2‐fold. Analysis of post‐CABG samples indicated marked elevations in HSP70 and Caspase‐3 protein compared to pre‐CABG values. This was only evident in the atria of aged individuals. Our data suggest that increased mitophagy flux could account for the reductions in mitochondrial markers in aged atria, and that CABG can induce a stress response leading to apoptosis signaling that is more prominent with age. Support or Funding Information Supported by NSERC Canada.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.